Non-alcoholic fatty liver diseases (NAFLDs) include a spectrum of fatty liver diseases in the absence of alcohol consumption, ranging from fatty liver to cirrhosis and hepatocellular carcinoma. Different degrees or types of NAFLDs include a) Steatosis b) Non-alcoholic steatoheapatitis (NASH) c) Fibrosis and d) cirrhosis e) Hepatocellular carcinoma. Steatosis is defined as triglyceride accumulation in hepatocytes or excess fat in liver. A minimum excess overload of fat of at least 5-10% than normal is considered significant condition of steatosis.
The second stage of NAFLD, Non alcohol steatoheapatitis (NASH), is a potentially serious condition that carries a substantial risk of progression to end stage Fibrosis, cirrhosis, and liver cancer or Hepatocellular carcinoma. The histopathological features of nonalcoholic steatoheapatitis (NASH) include hepatocellular steatosis and ballooning, mixed acute and chronic inflammation and perivenular, perisinusoidal collagen deposition. NASH is considered as the hepatic manifestation of metabolic disorder and is closely associated with type 2 diabetes, obesity, insulin resistance and systemic inflammatory state. The following prior art documents disclose the characteristic features of NAFLD and NASH    a) Williams, C. D., et al., Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology, 2011; 140(1): 124-31.    b) Charlton, M. R., et al., Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology, 2011; 141(4):1249-53.    c) Sanyal, A., et al., Population-based risk factors and resource utilization for HCC: US perspective. Curr Med Res Opin, 2010; 26(9):2183-91.    d) Ratziu, V., et al., A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol, 2010; 53(2): 372-84.    e) Yki-Jarvinen, H., Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol, 2014; 2(11): 901-10.
Evaluating the histopathology of NASH and NAFLD is important for determining the degree and progression of the disease. A histological ‘grading and staging” system has been developed to reflect the unique features of steatoheapatitis, gradations of severity and fibrosis, and to promote uniform reporting of the histopathology; (Brunt et al., Nonalcoholic steatoheapatitis: definition and pathology; Semin Liver Dis. 2001; 21(1):3-16), wherein a staging score reflects both location and extent of the disease.
Other NAFLDs may be differentiated from NASH by the NAFLD activity score (NAS), the sum of histopathology scores of a liver biopsy for Steatosis (0-3 grades), lobular inflammation (0-2), and hepatocellular ballooning (0-2). A NAS of less than 3 corresponds to NAFLD, 3-4 corresponds to borderline NASH, and greater than 5 corresponds to NASH. The biopsy is also scored for fibrosis (0-4). Similarly the grading system for ballooning and lobular inflammation, portal inflammation and steatosis grade is well explained and differentiated by Kleiner et al., Histology of NAFLD and NASH in adults and children, Clin Liver Dis. 2016; 20(2): 293-312.
Fibrosis occurs on further metabolic and biochemical abnormalities. It depends on the imbalance between the rate of formation and deposition of collagen. Fibrosis stages include stage 1, zone 3 perisinusoidal fibrosis; stage 2, perisinusoidal fibrosis with portal fibrosis; stage 3, as above with bridging fibrosis; and stage 4 as described by Brunt et al., Non alcoholic steatohepatits: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999; 94(9):2467-74. Fibrosis can be diagnosed in liver diseases using hydroxyproline and oxidative stress as biomarkers (Gabr et al., Prediction of fibrosis in hepatitis C. patients: assessments using hydroxyproline and oxidative stress biomarkers. Indian Virological Society 2013; 25(1): 91-100)
The oxidative stress markers also play a significant role in maintaining liver health. The importance of oxidative stress marker as non-invasive parameter for the assessment of liver fibrosis (Novitskiy G et al., Effects of ethanol and acetaldehyde on reactive oxygen species production in rat hepatic stellate cells Alcohol Clin Exp Res. 2006; 30(8):1429-35). Oxidative stress markers, antioxidant enzymes and hydroxyproline are documented to play a part in the pathogenesis of CHC. Clichici S et al., Non-invasive oxidative stress markers for liver fibrosis development in the evolution of toxic hepatitis. Acta Physiol Hung. 2011; 98(2):195-204)
NASH is usually a silent disease with minimum symptoms, while weight loss, fatigue and weakness develop as the disease progresses. Individuals with fatty liver of NAFLDs are determined to have elevated liver enzymes and lowering the liver enzyme population will correct or improve the liver condition. State-of-the art technique to manage enzyme count is to provide glutamine, a natural amino acid used as a nutritional supplement.
There is an urgent need for therapeutic management of NAFLDs. It is a significant burden to public health system, with no approved drugs for treatment. The primary mode of treatment is lifestyle management, while pioglitazone and Vitamin E have been used as pharmacotherapy to reduce hepatocellular injury, fibrosis and improve steatohepatitis. Other methods include using insulin sensitizers, biguanides eg. Metformin.
Natural molecules from different plant sources are also currently being used for hepatoprotection and for the management of NAFLDs (Madrigal-Santillán et al., Review of natural products with hepatoprotective effects, World J Gastroenterol. 2014; 20(40): 14787-14804). Curcumin from Curcuma sp. is well known for its therapeutic effect in mitigating the symptoms of NASH (Rahmani et al., Treatment of Non-alcoholic Fatty Liver Disease with Curcumin: A Randomized Placebo-controlled Trial, Phytotherapy Research, 2016; 30(9):1540-1548; Amato et al., NAFLD and Atherosclerosis Are Prevented by a Natural Dietary Supplement Containing Curcumin, Silymarin, Guggul, Chlorogenic Acid and Inulin in Mice Fed a High-Fat Diet, Nutrients 2017, 9(5), 492; https://doi.org/10.3390/nu9050492). Garcinol from Garcinia sp. is also a known hepatoprotective agent (WO2012092430A1). However, most of the natural molecules do not confer complete protection against all symptoms of NAFLDs. There still exists an unmet industrial need for a composition which is safe and reliable and elicits hepatoprotective ability by mitigating most of the symptoms associated with NAFLD and NASH.
The present invention provides a synergistic composition comprising curcuminoids and garcinol for the therapeutic management of NAFLDs and associated conditions like NASH, fibrosis and cirrhosis.
It is the principle object of the invention to disclose a synergistic hepatoprotective composition comprising 95% w/w Curcuminoids and 20% w/w Garcinol for the management of NAFDLs and associated conditions thereof.
It is yet another object of the invention to disclose a method for the therapeutic management of NAFLD and associated conditions like steatosis, NASH, fibrosis and cirrhosis using a composition comprising 95% w/w Curcuminoids and 20% w/w Garcinol.
The present invention solves the abovementioned objectives and provides further related advantages.